Asymmetric sequential allylic transfer reaction for the synthesis of 2-(1-stannylvinyl)-1,3-diols: Concise synthesis of (-)-avenaciolide and (-)-isoavenaciolide

Article abstract of DOI:10.1002/anie.200503863

(Chemical Equation Presented) More adventures of tin-tin: The stereo-specific synthesis of 2-stannylvinyl-1,3-diols was achieved through a one-pot allylic transfer/distannation/allylic transfer reaction sequence (see scheme). The method was applied to the concise asymmetric syntheses of (-)-avenaciolide and (-)-isoavenaciolide.

Full text of DOI:10.1002/anie.200503863

Angewandte
Chemie
Synthetic Methods
DOI: 10.1002/anie.200503863
Asymmetric Sequential Allylic Transfer Reaction
for the Synthesis of 2-(1-Stannylvinyl)-1,3-diols:
Concise Synthesis of (À)-Avenaciolide and
(À)-Isoavenaciolide**
Chan-Mo Yu,* Jinsuop Youn, and Juyoung Jung
Stereocontrolled consecutive processes can offer advantages
over stepwise transformations by increasing chemical efficacy
and saving efforts as a result of a simple operation.[1] During
the course of our research program aimed at developing new
synthetic methods for the stereoselective construction of
pyran rings through stepwise allylic transfer reactions,[2] we
disclosed our investigations on transition-metal-catalyzed
intramolecular allylations mainly between allene and carbon-
yl functionalities to afford cyclic compounds with high levels
of stereoselectivity.[3] With these observations in hand, we
became interested in designing a sequential allylic transfer
reaction from 1 with two aldehydes to form acyclic 2-(1-
stannylvinyl)-1,3-diols 2, which contain versatile functional
groups (Scheme 1).
Scheme 1. General strategy for the synthesis of 2, and thus natural
products 3 and 4, by a sequential approach. L*=chiral ligand.
It was envisaged that the sequential allylic transfer
reaction starting from 1 could be realized by a three-step
sequence as shown in Scheme 1. To provide direct access to 2,
we considered the bis(stannyl) compound A as a crucial
intermediate. The transformation involves propargylboration
[*] Prof. Dr. C.-M. Yu, J. Youn, J. Jung
Department of Chemistry and Institute of Basic Sciences
Sungkyunkwan University
Suwon 440-746 (Korea)
Fax: (+82)31-290-7075
E-mail: cmyu@chem.skku.ac.kr
[**] Generous financial support from the Korea Science & Engineering
Foundation (R01-2005-000-10381-0) and the Center for Molecular
Design and Synthesis (CMDS, KOSEF-SRC) at KAIST is gratefully
acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Communications
with an aldehyde to yield an allenic species, distannation of
at À408C. After cooling to À788C, benzaldehyde (1 equiv)
was added. Aqueous workup and silica gel chromatography
afforded 9a as a single stereoisomer in 77% isolated yield.
Note that although an excess of propargylborane 6 (1.3equiv)
was used, the formation of allenyl carbinol resulting from its
reaction with benzaldehyde was not observed. A control
experiment clearly revealed that the propargylborane 6 was
poisoned during the distannation process presumably by the
formation of 2,3-distannylallylborane, which does not react
with benzaldehyde at À788C.
the allene moiety using a palladium catalyst to form the allylic
tin reagent A, and a second allylic transfer reaction with
another aldehyde by activation of the existing boronyl group.
Thus, the boronyl moiety would play two important roles—as
a chiral controller and a Lewis acid promoter—to regulate
reactivity and stereoselectivity during the reaction sequence.
Herein, we report a one-pot sequential transformation for the
stereoselective synthesis of 2-(1-stannylvinyl)-1,3-diols with
the generation of three contiguous stereogenic centers, and
application of this method to the synthesis of (À)-avenacio-
lide and (À)-isoavenaciolide in three steps.
With the notion that this approach might lead to a general
and efficient method, we set out to determine the scope of the
reaction (Table 1). Indeed, the method is successful with a
We began with 5 and 6 for the first allylic transfer, as
developed by Corey et al.,[4] to give easy access to 7 with
excellent enantioselectivity (Scheme 2). Initial attempts of a
Table 1: Scope of the sequential allylic transfer reaction of 5 and (R,R)-
6.[a]
Entry
R1
R2
9
Yield [%][b]
1
2
3
4
5
6
7
8
9
PhCH2CH2
Ph
PhCH2CH2
PhCH2CH2
C5H11
Me2CHCH2
PhCH2CH2
PhCH2CH2
PhCH2CH2
Me2CH
Ph
a
b
c
d
e
f
g
h
i
77
68
78
81
73
68
71
72
63
66
74
PhCH2CH2
PhCH2CH2
C5H11
Ph
C5H11
Me2CHCH2
4-BrPh
C3H7CH CH
C5H11
Me2CH
Scheme 2. Preliminary investigations of the asymmetricsequential
allylictransfer reaction. Ts =p-toluenesulfonyl.
=
10
11
j
k
PhCH2CH2
[a] Reactions were run in CH2Cl2. Reagents and conditions: a) À108C,
11 h; b) À788C, 2 h; c) Me3SnSnMe3 (1.3 equiv), [(p-allyl)2Pd2Cl2]
(3 mol%), À408C, 4 h; d) À788C, 4 h. [b] Refers to yield after purifica-
tion.
distannation reaction of
7
(R1 = PhCH2CH2) with
Bu3SnSnBu3 in the presence of a palladium complex followed
by addition to benzaldehyde to give 9a were unsuccessful
under various reaction conditions, presumably owing to a lack
of reactivity caused by the steric bulkiness of the tributyl-
stannyl group.[5] We subsequently observed that the use of
Me3SnSnMe3 in the presence of [(p-allyl)2Pd2Cl2], which was
previously utilized for the cyclization of allene-aldehydes,[3a]
could also be employed for this purpose. Upon surveying
numerous conditions, the following observations emerged:
1) for the first allylic transfer, the use of 1.3equivalents of 5
and 6 was optimum to prevent subsequent addition of the
same aldehyde; 2) for the distannation reaction, the use of
3mol% of [( p-allyl)2Pd2Cl2] in CH2Cl2 at À408C for 4 h was
most efficient in terms of reaction yields; 3) the formation of 8
was confirmed by NMR spectroscopy after quenching with
pH 7 buffer solution; 4) only Me3SnSnMe3 proved to be
effective for the transformation; and 5) the use of CH2Cl2
resulted in optimum chemical yields in comparison to other
solvents.
variety of aldehydes to yield the 2-(1-stannylvinyl)-1,3-diols 9
in good yields. It is important to note that the reaction
produced no, or only detectable amounts (less than 1%), of
minor stereoisomers according to analysis by 1H NMR
spectroscopy and HPLC with chiral column (Chiralcel OD-
H or OD-RH) in comparison with authentic samples pre-
pared from (S,S)-6.
The stereochemical outcome for the transformations can
be explained by the analysis of stereochemical models as
depicted in Scheme 3.[6] There are two possibilities governing
the stereocontrol of the second allylic transfer reaction. First,
the remote stereogenic center attached to R1 was envisioned
to impact stereoselectivity during the allylic transfer through
the favored model 8C for 11. However, the results obtained
(Table 1, entries 1–3) did not support this claim: the stereo-
chemical relationship between 9a and 9b turned out to be
diastereomeric rather than enantiomeric, and 9c is an
optically active species. Therefore, the preference for the
absolute and relative configurations for adducts from (R,R)-8
with aldehydes could be explained on the basis of the
geometrical preference of the chairlike stereochemical
model 8A (Scheme 3). The stereoselectivity for both the
Under optimal conditions, the reaction was conducted by
dropwise addition of 5 (1.3equiv) to ( R,R)-6 (1.3equiv) at
À108C in CH2Cl2. After 11 h at À108C the reaction mixture
was cooled to À788C, and PhCH2CH2CHO (1 equiv) was
added during 2 h. To the resulting mixture was then added
Me3SnSnMe3 (1.3equiv) followed by [( p-allyl)2Pd2Cl2]
(3mol%), and the reaction mixture was maintained for 4 h
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Scheme 3. Stereochemical routes.
Scheme 4. Synthesis of (À)-avenaciolide (3) and (À)-isoavenaciolide
(4): a) NIS, À788C, 2 h, CH2Cl2; b) [Pd(PPh3)4] (2 mol%), CO
(100 atm), K2CO3, CH3CN, 708C, 1 h; c) NIS, À788C, 1 h, CH2Cl2, then
CF3CO2H (10 mol%), 2 h. NIS=N-iodosuccinimide.
first and second allylic transfer reactions must be controlled
by the chiral ligand. The exceptional stereoselectivity can also
be explained by assuming that a tight coordination of the
aldehyde to the boronyl moiety must be required for the
À
formation of the new C C bond, such that the overlap
3. For example, treatment of 14 with CO (10 atm) in the
presence of [Pd(PPh3)4] (2 mol%) and Et3N in CH3CN at
508C for 5 h afforded 3 and 15 in a ratio of 2:1 (71%). Longer
reaction times resulted in decomposition of the products.
Fortunately, we found that modified Stille conditions were
effective for our purpose.[10] Thus, treatment of 14 under an
atmosphere of CO (100 atm) in the presence of [Pd(PPh3)4]
(2 mol%) and K2CO3 in CH3CN at 708C for 1 h afforded (À)-
avenaciolide (3, 67%) along with 15 in a ratio of 95:5 as
judged by 1H NMR spectra of the crude mixture.
We then turned our attention to the synthesis of (À)-
isoavenaciolide (4). Compound 16 was obtained in moderate
(54%) yield, probably because intramolecular chelation of
the boronyl group with the ester in 8 resulted in diminished
reactivity with nonanal (12 h at À788C; Scheme 4). Treatment
of 16 with NIS to obtain the corresponding vinyl iodide 17
afforded a 1:1 mixture of 17 and the lactone 18. However,
after complete consumption of 16 in its reaction with NIS at
À788C for 1 h, addition of CF3CO2H (10 mol%) at À788C
resulted in the formation of 18 in 77% yield. A modified Stille
reaction of 18 completed the synthesis of 4.
between the carbonyl group and the double bond leads to
optimum stereoelectronic effects and minimum steric repul-
sions.
In light of the above results for the stereospecific
sequential allylic transfer reaction, we next turned our
attention to the application of this approach to the synthesis
of the natural products (À)-avenaciolide (3) and (À)-isoave-
naciolide (4; Scheme 1), which exhibit antifungal activities.[7]
Interestingly, the diastereomer 10 can be obtained simply by
changing the addition sequence of the aldehydes as illustrated
in Scheme 3. Thus, we envisaged that the enantioselective
synthesis of 3 and 4 could be realized by the sequential
addition of aldehydes and appropriate selection of the chiral
bromoborane 6 to obtain the correct absolute configurations.
À
Even though the C OH stereogenic center in 13 is not
matched with that in 3, we predicted that it could be
epimerized to the desired product owing to the greater
thermodynamic stability of a cis-fused bicyclic ring relative to
the trans isomer.
We undertook the synthesis of 3 from the allenylstannane
5 and (S,S)-6 as shown in Scheme 4. Lactone 13 was cleanly
obtained under standard conditions in 75% yield through the
sequential allylic transfer reaction. Conversion of 13 into 14
was achieved in 88% yield by using NIS.[8] Surprisingly, our
attempts to convert 14 into 3 under a CO atmosphere using
palladium catalysis according to standard procedures[9] were
not efficient in terms of the desired epimerization from 15 to
In summary, we have described a sequential allylic
transfer reaction for the synthesis of enantiomerically
enriched 2-(1-stannylvinyl)-1,3-diols which provides three
contiguous stereogenic centers through a four-component
assembly. The approach is efficient and promises to be
synthetically useful, as demonstrated here with the concise
syntheses of (À)-avenaciolide and (À)-isoavenaciolide.
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Communications
[3] a) C.-M. Yu, J. Youn, M.-K. Lee, Org. Lett. 2005, 7, 3733 – 3736;
b) C.-M. Yu, J. Youn, S.-K. Yoon, Y.-T. Hong, Org. Lett. 2005, 7,
4507 – 4510; c) C.-M. Yu, Y.-T. Hong, J. Lee, J. Org. Chem. 2004,
69, 8506 – 8509; d) S. Kang, Y.-T. Hong, J.-H. Lee, W.-Y. Kim, I.
Lee, C.-M. Yu, Org. Lett. 2003, 5, 2813– 2816.
[4] a) E. J. Corey, C.-M. Yu, D.-H. Lee, J. Am. Chem. Soc. 1990, 112,
878 – 879; b) E. J. Corey, C.-M. Yu, S. S. Kim, J. Am. Chem. Soc.
1989, 111, 5495 – 5496.
[5] For reviews, see: a) T. N. Mitchell, Synthesis 1992, 803– 815;
b) R. Zimmer, C. U. Dinesh, E. Nandann, F. A. Khan, Chem.
Rev. 2000, 100, 3067 – 3125; c) T. Mandai, in Modern Allene
Chemistry, Vol. 2 (Eds.: N. Krause, A. S. K. Hashmi), Wiley-
VCH, Weinheim, 2004, pp. 925 – 972.
Experimental Section
General procedure—preparation of 9a from (R,R)-6: A flame-dried
20-mL Schlenk flask containing (+)-(1R,2R)-1,2-diphenyl-1,2-bis-p-
toluenesulfonylamide (0.50 g, 0.96 mmol) was charged with dry
CH2Cl2 (7 mL), and the resulting mixture was cooled to 08C and
treated with BBr3 (1.1 mL of a freshly prepared 1m solution in
CH2Cl2, 1.1 mmol). The solution was stirred at 08C for 1 h, warmed to
208C and maintained at this temperature for 5 h, and then concen-
trated under vacuum (1 mmHg). Dryness of the vacuum line was
maintained with a drying tube containing anhydrous CaSO4 and two
traps (one containing NaOH pellets, and the other a cold trap at
À788C). Freshly distilled CH2Cl2 (5 mL) was added and evaporated
under vacuum as above.
[6] For discussions on the mechanism of allylations, see: a) M.
Santelli, J.-M. Pons, Lewis Acids and Selectivity in Organic
Synthesis, CRC Press, Boca Raton, 1996, pp. 91 – 184; b) S. E.
Denmark, N. G. Almstead in Modern Carbonyl Chemistry (Ed.:
J. Otera), Wiley-VCH, Weinheim, 2000, pp. 299 – 401; c) S. R.
Chemler, W. R. Roush in Modern Carbonyl Chemistry (Ed.: J.
Otera), Wiley-VCH, Weinheim, 2000, pp. 403– 490; d) J. A.
Marshall, Chem. Rev. 2000, 100, 3163 – 3185.
[7] a) V. K. Aggarwal, P. W. Davies, A. T. Schmidt, Chem. Commun.
2004, 1232 – 1233; b) E. Alcazar, M. Kassou, I. Metheu, S.
Castillon, Eur. J. Org. Chem. 2000, 2285 – 2289; c) M.-J. Chen, K.
Narkuran, R.-S. Liu, J. Org. Chem. 1999, 64, 8311 – 8318; d) V. S.
Martin, C. M. Rodriguez, T. Martin, Org. Prep. Proced. Int. 1998,
30, 291 – 323, and references therein.
Freshly distilled CH2Cl2 (4 mL) was again added to the residue,
and the homogeneous solution of (R,R)-6 was cooled to À108C and
treated dropwise with 1,2-propadienyl-tributylstannane (5, 0.33 g,
1.00 mmol) in CH2Cl2 (1 mL). The reaction mixture was maintained
at À108C overnight (ca. 11 h) and then cooled to À788C. A solution
of hydrocinnamaldehyde (purified and distilled, 100 mg, 0.74 mmol)
in CH2Cl2 (1 mL) was added over 10 min to the cooled reaction
mixture along the wall of the flask while keeping the temperature
below À788C. The mixture was then stirred for 2 h, then hexame-
thyldistannane (0.21 mL, 0.33 g, 1.01 mmol) in CH2Cl2 (0.5 mL) was
added followed by [(p-allyl)2Pd2Cl2] (8.3mg, 0.022 mmol) in CH 2Cl2
(0.5 mL). The mixture was then allowed to warm to À408C and was
stirred for 4 h.
The resulting solution of 8 was cooled to À788C, and a solution of
benzaldehyde (0.08 mL, 83.6 mg, 0.78 mmol) in CH2Cl2 (1 mL) was
added dropwise to the flask. The reaction was allowed to proceed for
4 h at À788C and then quenched by addition of aqueous buffer
solution (pH 7, 10 mL) followed by CH2Cl2 (ca. 10 mL) to dissolve the
white bis(sulfonamide) precipitate. The aqueous layer was extracted
with CH2Cl2 (ca. 10 mL ” 2), and the combined organic extracts were
washed with saturated solutions of NaHCO3 (1 ” ) and NaCl (1 ” ),
dried over anhydrous Na2SO4, and filtered. The solvents were
evaporated, and the residue was taken up in diethyl ether (ca.
30 mL). The solution was cooled to 08C for 20 min to complete the
precipitation of (+)-(1R,2R)-1,2-diphenyl-1,2-bis-p-toluenesulfonyla-
mide, which was then removed by filtration through a sintered glass
funnel. The filtrate was washed with cold 20% KF solution (1 ” ) and
saturated aqueous NaHCO3 solution (1 ” ). The organic layer was
separated, dried over anhydrous Na2SO4, filtered, and concentrated
under reduced pressure to give the crude product. Final purification
was effected by SiO2 chromatography (4:1 hexanes/EtOAc) to afford
pure 9a as a colorless oil (0.255 g, 0.57 mmol, 77%).
[8] a) R. A. Britton, E. Piers, B. O. Patrick, J. Org. Chem. 2004, 69,
3068 – 3075; b) R. S. Paley, A. De Dios, L. A. Estroff, J. A.
Lafontaine, C. Montero, D. J. McCulley, M. B. Rubio, M. P.
Ventura, H. L. Weers, R. F. de la Pradilla, S. Castro, R. Dorado,
M. Morente, J. Org. Chem. 1997, 62, 6326 – 6343.
[9] V. Farina, M. Eriksson in Handbook of Organopalladium
Chemistry for Organic Synthesis, Vol. II (Eds.: E. Negishi, A.
de Meijere), Wiley-Interscience, New York, 2002, pp. 2351 –
2355.
[10] L. D. Martin, J. K. Stille, J. Org. Chem. 1982, 47, 3630 – 3633.
Received: November 1, 2005
Revised: November 29, 2005
Keywords: asymmetricsynthesis · boranes · natural products ·
.
syntheticmethods · tin
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